2.1. Introduction
While the widespread use of antibiotics since the 1940s has greatly reduced human morbidity and mortality, [1] bacterial resistance to these drugs has more than kept pace with antibacterial development. [2] From first-line treatments for routine infections to last resort antibiotics for life threatening infections, microbial resistance to antibacterial drugs is removing treatment options from doctors across the globe. Traditional antibiotics target a variety of processes that are essential for rapid bacterial growth, including inhibition of DNA/RNA synthesis (fluoroquinolones,) the depolarization of membrane potentials (daptomycin), inhibition of protein synthesis (aminoglycosides), [3] and inhibition of cell wall synthesis (β-lactams). Antibiotic resistance is achieved in a number of ways. With regard to the β-lactam class, some resistant bacteria produce enzymes called β-lactamases that selectively hydrolyze β-lactam antibiotics, rendering them ineffective at inhibiting cell wall biosynthesis. Thus, bacteria that produce β-lactamases can survive, or are resistant to, β-lactam antibiotics. [4] Alarmingly, bacterial resistance to β-lactam and other antibiotics continues to rise across the world. [5]
Antibiotic research has historically been directed at the discovery of new classes of broad-spectrum antibiotics. Recently, the search for new classes of antibiotics has been frustratingly slow. Indeed, since 1962 only two new classes of antibiotics have reached the market. [2] Conversely, the synthetic production of analogues to current antibiotics has been more fruitful. Indeed, the production of cephalosporin analogues has kept the cephalosporin class of antibiotics at the forefront of the fight against resistance. The downfall to this strategy is that there are a limited number of analogues for any particular class and that, given enough time, bacteria will develop resistance to each one.
The battle against antibacterial resistance is being waged on multiple fronts. By rotating through several rounds of different classes of antibiotics, alternating therapy has showed some promise. [6] Some scientists have begun searching for virulence targets rather than drugs that target viability. [3] Still, the world is in urgent need of new antibiotics and searching for new targets will take time. One potential solution is to develop an antibiotic that has multiple targets. Because it is harder for bacteria to develop resistance to multiple antibiotic mechanisms simultaneously, combination therapy or an antibiotic that has multiple targets should show increased activity and longevity.
Because metals play such important roles in cellular functions, their homeostasis presents a promising target for developing new antibiotics. [8, 9, 10] Numerous prescribed antibiotics have metal chelating properties and some metal chelators such as 2-mercaptopyridine N-oxide (pyrithione) and hydroxyquinolines are known to be bactericidal. [11, 12] However, metal ions are also necessary for normal mammalian cell function so systemic application of metal chelators can be problematic. In order to avoid undesired metal chelation, a number of prochelators have been developed that have little affinity for metals until they have been activated. [13, 14]